Effect of a new PPAR-gamma agonist, lobeglitazone, on neointimal formation after balloon injury in rats and the development of atherosclerosis

Lim, Soo; Lee, Kuy Sook; Lee, Jie Eun; Park, Ho Seon; Kim, Kyoung Min; Moon, Jae Hoon; Choi, Sung Hee; Park, Kyong Soo; Kim, Young–Bum; Jang, Hak Chul

doi:10.1016/j.atherosclerosis.2015.08.037

Cited by 52 publications

(49 citation statements)

References 47 publications

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“…This finding is consistent with previous reports in Caco-2 cells and HUVECs. 26,27 IL-1β-induced nuclear p65 protein was also decreased by pioglitazone in vascular SMC from hypertensive rats. 28 The functional importance of PPARγ to accelerate nuclear export of p65 is further illustrated by our finding that WT-PPARγ-mediated reduction in NF-κB target gene expression can be impaired by pharmacological inhibition of nuclear export.…”

Section: Discussionmentioning

confidence: 87%

Hypertension-Causing Mutation in Peroxisome Proliferator–Activated Receptor γ Impairs Nuclear Export of Nuclear Factor-κB p65 in Vascular Smooth Muscle

Mukohda

Guo

et al. 2017

Hypertension

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Selective expression of dominant negative (DN) peroxisome proliferator-activated receptor gamma (PPARγ) in vascular smooth muscle cells (SMC) results in hypertension, atherosclerosis, and increased NF-κB target gene expression. Mesenteric SMC were cultured from mice designed to conditionally express wild-type (WT) or DN-PPARγ in response to Cre-recombinase to determine how SMC PPARγ regulates expression of NF-κB-target inflammatory genes. SMC-specific overexpression of WT-PPARγ or agonist-induced activation of endogenous PPARγ blunted TNFα-induced NF-κB target gene expression and activity of a NF-κB responsive promoter. TNFα-induced gene expression responses were enhanced by DN-PPARγ in SMC. Although expression of NF-κB p65 was unchanged, nuclear export of p65 was accelerated by WT-PPARγ and prevented by DN-PPARγ in SMC. Leptomycin B, a nuclear export inhibitor, blocked p65 nuclear export and inhibited the anti-inflammatory action of PPARγ. Consistent with a role in facilitating p65 nuclear export, WT-PPARγ co-immunoprecipitated with p65, and WT-PPARγ was also exported from the nucleus after TNFα treatment. Conversely, DN-PPARγ does not bind to p65 and was retained in the nucleus after TNFα treatment. Transgenic mice expressing WT- or DN-PPARγ specifically in SMC (S-WT or S-DN) were bred with mice expressing luciferase controlled by a NF-κB-responsive promoter to assess effects on NF-κB activity in whole tissue. TNFα-induced NF-κB activity was decreased in aorta and carotid artery from S-WT, but was increased in vessels from S-DN mice. We conclude that SMC PPARγ blunts expression of pro-inflammatory genes by inhibition of NF-κB activity through a mechanism promoting nuclear export of p65, which is abolished by DN mutation in PPARγ.

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Section: Discussionmentioning

confidence: 87%

Hypertension-Causing Mutation in Peroxisome Proliferator–Activated Receptor γ Impairs Nuclear Export of Nuclear Factor-κB p65 in Vascular Smooth Muscle

Mukohda

Guo

et al. 2017

Hypertension

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“…Aortic atherosclerosis in ApoE −/− mice To measure the atherosclerotic lesion area, the aortic arch prepared using the en face method was stained with Oil Red O solution. [18]. Atheroma composition around the aortic valve area was measured by the same method using Oil Red O staining to identify lipid droplets, Masson's trichrome staining to identify fibrous tissue and CD68 (1:200) immunofluorescence to identify inflammatory cell infiltration.…”

Section: Animal Studymentioning

confidence: 99%

The beneficial effects of empagliflozin, an SGLT2 inhibitor, on atherosclerosis in ApoE −/− mice fed a western diet

et al. 2016

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“…In the balloon injury rat model, lobeglitazone-treated rats showed less neointimal formation in the carotid artery than placebo-treated rats. Lobeglitazone treatment also reduced the atheromatous burden in the aorta of apolipoprotein E knockout mice fed a high-fat and high cholesterol diet [18]. However, there are no human or animal studies on any potential renal protective effects of lobeglitazone.…”

Section: Introductionmentioning

confidence: 99%

Lobeglitazone, a Novel Peroxisome Proliferator-Activated Receptor γ Agonist, Attenuates Renal Fibrosis Caused by Unilateral Ureteral Obstruction in Mice

et al. 2017

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BackgroundRenal tubulointerstitial fibrosis is a common feature of the final stage of nearly all cause types of chronic kidney disease. Although classic peroxisome proliferator-activated receptor γ (PPARγ) agonists have a protective effect on diabetic nephropathy, much less is known about their direct effects in renal fibrosis. This study aimed to investigate possible beneficial effects of lobeglitazone, a novel PPARγ agonist, on renal fibrosis in mice.MethodsWe examined the effects of lobeglitazone on renal tubulointerstitial fibrosis in unilateral ureteral obstruction (UUO) induced renal fibrosis mice. We further defined the role of lobeglitazone on transforming growth factor (TGF)-signaling pathways in renal tubulointerstitial fibrosis through in vivo and in vitro study.ResultsThrough hematoxylin/eosin and sirius red staining, we observed that lobeglitazone effectively attenuates UUO-induced renal atrophy and fibrosis. Immunohistochemical analysis in conjunction with quantitative reverse transcription polymerase chain reaction and Western blot analysis revealed that lobeglitazone treatment inhibited UUO-induced upregulation of renal Smad-3 phosphorylation, α-smooth muscle actin, plasminogen activator inhibitor 1, and type 1 collagen. In vitro experiments with rat mesangial cells and NRK-49F renal fibroblast cells suggested that the effects of lobeglitazone on UUO-induced renal fibrosis are mediated by inhibition of the TGF-β/Smad signaling pathway.ConclusionThe present study demonstrates that lobeglitazone has a protective effect on UUO-induced renal fibrosis, suggesting that its clinical applications could extend to the treatment of non-diabetic origin renal disease.

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Effect of a new PPAR-gamma agonist, lobeglitazone, on neointimal formation after balloon injury in rats and the development of atherosclerosis

Cited by 52 publications

References 47 publications

Hypertension-Causing Mutation in Peroxisome Proliferator–Activated Receptor γ Impairs Nuclear Export of Nuclear Factor-κB p65 in Vascular Smooth Muscle

Hypertension-Causing Mutation in Peroxisome Proliferator–Activated Receptor γ Impairs Nuclear Export of Nuclear Factor-κB p65 in Vascular Smooth Muscle

The beneficial effects of empagliflozin, an SGLT2 inhibitor, on atherosclerosis in ApoE −/− mice fed a western diet

Lobeglitazone, a Novel Peroxisome Proliferator-Activated Receptor γ Agonist, Attenuates Renal Fibrosis Caused by Unilateral Ureteral Obstruction in Mice

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